New approaches for the discovery of antibacterial drugs are paramount to our efforts in the continuing fight against bacterial resistance. In this regard, enzyme inhibitors that selectively target a bacterial enzyme over their human counterpart offer unique opportunities for such selective inhibition approaches. Bacterial DNA topoisomerases are one such class of enzymes that help in regulating DNA topology (Tse-Dinh, Y. Infect. Disord.: Drug Targets (2007) 7, 3-9; Tse-Dinh, Y. Nucleic Acids Research (2009) 37, 731-737). The cellular functions of topoisomerases include relaxing (+) and (−) supercoil in DNA as well as in introducing supercoils to their DNA substrates (Champoux, J. J. Annu. Rev. Biochem. (2001), 70, 369-413). These functions of DNA topoisomerases can be used to develop anticancer or antibacterial agents (Tse-Dinh, Y. Nucleic Acids Research (2009) 37, 731-737; Pommier, Y. Chem. Rev. (2009) 109, 2894-2902). The therapeutic interest in the development of small molecules as inhibitors of DNA topoisomerase lies in their ability to act as both cleavable complex stabilizing agents as well as in their ability to bind at the ATP binding site (Tse-Dinh, Y. Nucleic Acids Research (2009) 37, 731-737).
A number of small molecules have been discovered that poison the functions of DNA topoisomerases. These include camptothecin and its derivatives, intercalators and compounds that interact with the minor groove of B-DNA such as bisbenzimidazoles (Hsiang Y. H. et al., Journal of Biological Chemistry (1985) 260, 14873-14878; Bailly, C., Targeting DNA and topoisomerase I with indolocarbazole antitumor agents. In Small Molecule DNA and RNA Binders (2003) Vol. 2; 2, pp 538-575; Bailly, C., Curr. Med. Chem. (2000) 7, 39-58; Hande, K. R., Eur. J. Cancer (1998) 34, 1514-1521; Xu, Z. et al., Biochemistry (1998) 37, 3558-3566; Froelich-Ammon, S. J. and Osheroff, N., J. Biol. Chem. (1995) 270, 21429-32; Chen, A. Y. et al., Proceedings of the National Academy of Sciences (1993) 90, 8131-8135; Chen, A. Y. et al., Cancer Research (1993) 53, 1332-1337). Benzimidazoles are an important class of compounds that display a widespread range of biological activities. Halogenated monobenzimidazoles have shown antimycobacterial activity better than isoniazid (Kazimierczuk, Z. et al., Eur. J. Med. Chem. (2005) 40, 203-208). Similarly, triazolyl derivatized monobenzimidazoles have displayed antimicrobial properties (Jadhav, G. R. et al., Eur. J. Med. Chem. (2009) 44, 2930-2935). In comparison to abundant literature reports on the biological properties of monobenzimidazoles, studies on the antimicrobial properties of bisbenzimidazoles (particularly those modeled from Hoechst 33258) are very limited (Chen, A. Y. et al., Cancer Research (1993) 53, 1332-1337; Bansal, S. et al., Int. J. Antimicrob. Agents (2010) 35, 186-190). Hoechst 33258 is a bisbenzimidazole compound that has been a subject of intense study for over three decades due to its binding to AT rich duplex DNA structures (Willis, B. and Arya, D. P., Biochemistry (2010) 49, 452-469; Willis, B. and Arya, D. P., Biochemistry (2006) 45, 10217-10232; Correa, B. J. et al., Bioorg. Med. Chem. Lett. (2006) 16, 3745-3750).